Vessel Remodeling Research Articles

Significance of serum Krebs von den Lungen-6 in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a well-known multi-system connective tissue disease, it has an unidentified aetiology that is characterised by abnormal immune system activation, vascular injury, which may progress to faulty neovascularization and inadequate vessel remodelling, and tissue scarring of the skin, lungs, and other internal viscera. Krebs von den Lungen-6 is a kind of transmembrane glycoprotein of type II alveolar epithelial cells and is specific for determining its damage. Regardless of the cause, serum Krebs von den Lungen-6 levels have been investigated in interstitial lung disease (ILD) of several etiologies and have been found to be a significant serum marker for ILD. The current research aims to look into the relationship between serum Krebs von den Lungen-6 levels and disease severity and clinical manifestations, specifically interstitial pulmonary fibrosis, in patients with SSc. In this study, 30 patients with systemic sclerosis and 30 control subjects—15 dermatomyositis patients and 15 healthy volunteers— were also incorporated to see if the change in serum Krebs von den Lungen-6 levels is specific for SSc as dermatomyositis is another connective tissue disorder with lung affection.ResultsA statistically significant difference (P < 0.001) in the median value of Krebs von den Lungen-6 when compared to the control groups was observed, which was 447.95 (145.68–817.98) in the SSc patients group, 158.80 (130.00–730.70) in the dermatomyositis group, and 48.10 (39.50–103.90) in the healthy control group. A significantly higher median value of Krebs von den Lungen-6 in ground glass, honeycombing, and nodular HRCT was established, with P-value (P < 0.001). There was a highly statistically significant discrepancy in the median Krebs von den Lungen-6 value between patients with ILD (717.7) and patients without ILD (145.7) with P-value (P < 0.001). A statistically significant positive correlation was found between Krebs von den Lungen-6 (U/ml) and Disease duration (years), Medsger severity scale, Digital ulceration, modified Rodnan skin score (MRSS), and P-value (P < 0.05).ConclusionKrebs von den Lungen-6 could be a scleroderma biomarker. It has been linked to the development and severity of interstitial lung disease in systemic sclerosis patients and may shed light on the pathophysiology of some fibrotic lung changes.

Canagliflozin ameliorates hypobaric hypoxia-induced pulmonary arterial hypertension by inhibiting pulmonary arterial smooth muscle cell proliferation

ABSTRACT Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.

Abstract 12878: Inhibition of NK1.1 Signaling Attenuates Pressure Overload-Induced Cardiopulmonary Inflammation, Pulmonary IFN-γ Production, and Heart Failure Progression

Introduction: Inflammation contributes to heart failure (HF) development, the progression from left ventricular failure to pulmonary remodeling, and the consequent right ventricular hypertrophy and failure. Hypothesis: NK1.1 plays a critical role in Natural killer (NK) and NK T (NKT) cells, but the role of NK1.1 in HF development and progression is unknown. Methods: We studied the effects of NK1.1 inhibition on transverse aortic constriction (TAC)-induced cardiopulmonary inflammation, HF development, and HF progression in immunocompetent male mice of C57BL/6J background. Results: We found that NK1.1 + cell-derived interferon gamma + (IFN-γ + ) was significantly increased in pulmonary tissues after HF. In addition, anti-NK1.1 antibodies simultaneously abolished both NK1.1 + cells, including the NK1.1 + NK and NK1.1 + NKT cells in peripheral blood, spleen, and lung tissues, but had no effect on cardiopulmonary structure and function under control conditions. However, inhibition of NK1.1 signaling by anti-NK1.1 antibodies significantly rescued mice from TAC-induced left ventricular inflammation, fibrosis, and failure. Inhibition of NK1.1 signaling also significantly attenuated TAC-induced pulmonary leukocyte infiltration, fibrosis, vessel remodeling, and consequent right ventricular hypertrophy. Moreover, inhibition of NK1.1 signaling significantly reduced TAC-induced pulmonary macrophage and dendritic cell infiltration and activation. Conclusions: Our data suggest that inhibition of NK1.1 signaling is effective in attenuating systolic overload-induced cardiac fibrosis, dysfunction, and consequent pulmonary remodeling in immunocompetent mice through modulating the cardiopulmonary inflammatory response.

Abstract 15534: Identification of Narciclasine, a Potential Drug to Treat PAH by Unbiased Pharmaco-Transcriptomic Study

Introduction: Pulmonary arterial hypertension (PAH) is a life-threatening vascular disorder characterized by persistent vasoconstriction and detrimental remodeling of the pulmonary blood vessels. This incurable disease is marked by a complex gene expression reprogramming that triggers, among other, metabolic disorders, heightened by inflammation, and the development of a pro-survival phenotype in pulmonary arterial smooth muscle cells (PASMC).We conducted an unbiased transcriptomic study using lung samples from 16 PAH patients and 12 non-PAH controls and identified 4013 differentially expressed genes. Leveraging in silico pharmaco-transcriptomic analysis (utilizing the Lincs and Sigcom databases), we identified narciclasine as a potential drug. Hypothesis: Consequently, we hypothesized that narciclasine could offer improvements in PAH. Methods and Results: In vivo , we administered narciclasine treatment (1 mg/kg, 2 weeks, gavage) in a murine model of PH (monocrotaline model, 60 mg/kg, sc.) and observed improved PH hemodynamics (RVSP, PAAT, TPR), reduced inflammation (CD68 immunofluorescence (IF)), decreased PASMC survival (PCNA and cleaved caspase 3 IF), and alleviated adverse vascular remodeling (Elastic van Gieson Stain Kit). In vitro , narciclasine exhibited a dose-dependent reduction of cell proliferation (IF: ki67; Western blot Survivin, PCNA and PLK1) and increased apoptosis PAH-PASMC (IF: cleaved caspase 3; Wb: Bax and Bcl2). Transcriptomic study (conducted in treated PASMCs) reveals that the therapeutic effects of narciclasine in PAH may be attributed to decreased glycosylation (Gene Ontology analysis). We further observed increased glycosylation in remodeled arteries from PAH lungs, PH preclinical models, and cultured PASMC (Periodic Acid Schiff Kit). Subsequently, we validated that narciclasine reduced glycosylation and downregulated the expression of glycosylation enzymes (by wb: GFAT, NGT, OGT) both in vitro and in vivo. Statistical tests used: unpaired t (2 groups), ANOVA (&gt; 2 groups). Conclusions: In conclusion, our unbiased pharmaco-transcriptomic study identifies narciclasine as a potential therapeutic drug for PAH. Notably, its efficacy appears to be mediated by the reduction of glycosylation.

Abstract 18479: Lack of Catalytic and Non-Catalytic Function of PI3 Kinase Gamma in Mice Increases Hypoxia-Induced Pulmonary Hypertension

Rationale: Pulmonary hypertension (PH) is characterised by vasoconstriction and remodelling of pulmonary vessels, leading to elevated pulmonary arterial pressure and right ventricular (RV) hypertrophy. PI 3-kinase γ (PI3Kγ) is expressed in leukocytes, cardiomyocytes, and endothelial cells (EC) which are all involved in the pathogenesis of PH. The catalytic function of PI3Kγ is involved in leukocyte recruitment and EC proliferation which are important for vascular remodelling and maladaptive cardiac hypertrophy whereas its non-catalytic function affects cardiac contractility via cAMP signaling. Furthermore, inactivation of PI3Kγ impairs nitric oxide production by eNOS, which may lead to increased vascular resistance. Therefore, we investigated the role of both catalytic and non-catalytic functions of PI3Kγ in the pathogenesis of PH. Methods: PI3Kγ knockout mice (PI3Kγ -/- ), as well as mice with a catalytically inactive form of PI3Kγ (PI3Kγ KD/KD ) were exposed to hypoxia-induced PH (21 days at 10% O 2 hypoxia (HOX)). Systolic right ventricular pressure (RVSP) was measured using a Millar pressure catheter inserted via the jugular vein. RV hypertrophy was determined by Fulton's index. Results: PI3Kγ -/- mice showed significantly increased RVSP after hypoxia compared to WT controls (HOX WT 34.16±3.21 mmHg vs HOX PI3Kγ -/- 37.04±2.31 mmHg; p=0.0049). Already under normoxia (NOX), an increased RVSP was measured in PI3Kγ -/- mice (NOX WT 26.13±1.2mmHg vs. NOX PI3Kγ -/- 28.07±0.88 mmHg, p=0.0157). A significant increase in RVSP was also detected in PI3Kγ KD/KD (HOX WT 34.67±2.02 mmHg vs. HOX PI3Kγ KD/KD 37.95±1.39 mmHg; p=0.0228). Here, a significant increase in RV hypertrophy was evident for PI3Kγ KD/KD mice (HOX WT 0.38±0.06 vs. HOX PI3Kγ KD/KD 0.46±0.09; p=0.0037) which was not detected in PI3Kγ -/- compared to WT controls after hypoxia. Conclusion: The results show that both catalytic and non-catalytic inactivation of PI3Kγ in vivo do not counteract the pathogenesis of PH, but conversely enhance it. In this context, reduced phosphorylation of eNOS may play a crucial role, leading to increased vasoconstriction, whereas increased cAMP levels in PI3Kγ -/- may help the RV to adapt to the increased pressure. The exact mechanisms will be analysed in the future.

Abstract 13128: IGFBP8 as a Novel Biomarker for Hemodynamics and Functional Status in Pulmonary Arterial Hypertension

Background: Previous studies have shown that insulin-like growth factor binding proteins (IGFBPs) are correlated with pulmonary artery hypertension (PAH) disease severity. IGFBP8 has been shown in- vitro to be associated with pulmonary vessel remodeling and PAH in gene deletion experiments. However, no studies have evaluated IGFBP8 levels in adults with PAH. Research Question: This study sought to assess if IGFBP8 concentrations are elevated in patients with PAH and if levels are associated with survival, hemodynamic, and clinical PAH measurements. Methods: Serum IGFBP8 was measured in 2,763 adults with PAH and 92 adult controls. Two PAH cohorts and two control cohorts were used for analysis. A Mann-Whitney U test was used to compare IGFBP8 levels in PAH and controls. Samples were adjusted for age and sex using linear and logistic regression for continuous and categorical variables, respectively. IGFBP8 levels in the PAH cohort were compared to mean right atrial (mRAP), mean pulmonary artery pressures (mPAP), pulmonary vascular resistance (PVR) and functional measures such as six-minute walk distance (6-MWD), and New York Heart Association Functional Class (NYHA FC). Analysis of composite outcome (death or transplant) was conducted using a Cox proportional hazard model. Results: IGFBP8 levels were higher in PAH vs controls patients (Figure 1B, p&lt;0.0001). Among PAH patients, for every natural log unit higher, IGFBP8 was associated with death or transplant with Cox proportional hazard ratio of 1.313 (95% CI 1.034-1.666; p=0.025). Higher IGFBP8 levels were associated with lower 6-MWD (p=0.035) and increased NYHA FC (p=0.026). Hemodynamically, increased IGFBP8 levels were associated with lower cardiac index (p=0.014), increased mRAP (p=0.012) and lower stroke volume (p=0.002) but not mPAP or PVR (Figure 1A). Conclusions: IGFBP8 is a novel biomarker in PAH. Higher levels are associated with worse survival, worse hemodynamics, and poor functional status.

Chronic intermittent hypoxia-induced cardiovascular and renal dysfunction: from adaptation to maladaptation.

Chronic intermittent hypoxia (CIH) is the dominant pathological feature of human obstructive sleep apnoea (OSA), which is highly prevalent and associated with cardiovascular and renal diseases. CIH causes hypertension, centred on sympathetic nervous overactivity, which persists following removal of the CIH stimulus. Molecular mechanisms contributing to CIH-induced hypertension have been carefully delineated. However, there is a dearth of knowledge on the efficacy of interventions to ameliorate high blood pressure in established disease. CIH causes endothelial dysfunction, aberrant structural remodelling of vessels and accelerates atherosclerotic processes. Pro-inflammatory and pro-oxidant pathways converge on disrupted nitric oxide signalling driving vascular dysfunction. In addition, CIH has adverse effects on the myocardium, manifesting atrial fibrillation, and cardiac remodelling progressing to contractile dysfunction. Sympatho-vagal imbalance, oxidative stress, inflammation, dysregulated HIF-1α transcriptional responses and resultant pro-apoptotic ER stress, calcium dysregulation, and mitochondrial dysfunction conspire to drive myocardial injury and failure. CIH elaborates direct and indirect effects in the kidney that initially contribute to the development of hypertension and later to chronic kidney disease. CIH-induced morphological damage of the kidney is dependent on TLR4/NF-κB/NLRP3/caspase-1 inflammasome activation and associated pyroptosis. Emerging potential therapies related to the gut-kidney axis and blockade of aryl hydrocarbon receptors (AhR) are promising. Cardiorenal outcomes in response to intermittent hypoxia present along a continuum from adaptation to maladaptation and are dependent on the intensity and duration of exposure to intermittent hypoxia. This heterogeneity of OSA is relevant to therapeutic treatment options and we argue the need for better stratification of OSA phenotypes.

Benefits of topical indigo naturalis nanofibrous patch on psoriatic skin: A transdermal strategy for botanicals.

Indigo naturalis (IN) has been extensively used as a topical treatment for psoriasis. However, clinical applications of IN in ointment were hampered by its limited transdermal efficiency and dark stains. To address the aforementioned issues, nanopatches carrying IN were fabricated using poly(ε-caprolactone, PCL)/poly(ethylene oxide, PEO) and topically applied to psoriasiform skin. The ideal ratio of 5% PCL/PEO was established to be 80:20 (w/w), and 15% IN as payload was confirmed. Investigations on the three principal active components of IN release indicated that indirubin and tryptanthrin were released in bursts, while indigo was released in a limited and controlled manner. Further biological analyses confirmed a favorable biocompatibility of amphiphilic IN-PCL/PEO, which coincided with the intended therapeutic outcomes as measured by severity index scoring and pathological evaluations in vivo. The advantages of IN as nanopatches over ointment could be due to improved transdermal distribution of indirubin and tryptanthrin, resulting in effective management of epidermal hyperplasia and blood vessel remodeling. Meanwhile, due to the lower preservation of epidermal indigo, IN-PCL/PEO nanopatches caused no skin coloration. Similarly, during a 4-week topical treatment of IN-PCL/PEO nanopatches, the safety and anti-psoriatic benefits were obtained in an initial human test. The conversion of IN from topical cream to electrospun nanofibers opens up new avenues for bench-to-bedside translation of this herbal therapy and provides mechanistic insight into IN's roles in the management of psoriasis.

Senescent Cells: Dual Implications on the Retinal Vascular System.

Cellular senescence, a state of permanent cell cycle arrest in response to endogenous and exogenous stimuli, triggers a series of gradual alterations in structure, metabolism, and function, as well as inflammatory gene expression that nurtures a low-grade proinflammatory milieu in human tissue. A growing body of evidence indicates an accumulation of senescent neurons and blood vessels in response to stress and aging in the retina. Prolonged accumulation of senescent cells and long-term activation of stress signaling responses may lead to multiple chronic diseases, tissue dysfunction, and age-related pathologies by exposing neighboring cells to the heightened pathological senescence-associated secretory phenotype (SASP). However, the ultimate impacts of cellular senescence on the retinal vasculopathies and retinal vascular development remain ill-defined. In this review, we first summarize the molecular players and fundamental mechanisms driving cellular senescence, as well as the beneficial implications of senescent cells in driving vital physiological processes such as embryogenesis, wound healing, and tissue regeneration. Then, the dual implications of senescent cells on the growth, hemostasis, and remodeling of retinal blood vessels are described to document how senescent cells contribute to both retinal vascular development and the severity of proliferative retinopathies. Finally, we discuss the two main senotherapeutic strategies-senolytics and senomorphics-that are being considered to safely interfere with the detrimental effects of cellular senescence.

Pump-Less Platform Enables Long-Term Recirculating Perfusion of 3D Printed Tubular Tissues.

The direction and pattern of fluid flow affect vascular structure and function, in which vessel-lining endothelial cells exhibit variable cellular morphologies and vessel remodeling by mechanosensing. To recapitulate this microenvironment, some approaches have been reported to successfully apply unidirectional flow on endothelial cells in organ-on-a-chip systems. However, these platforms encounter drawbacks such as the dependency on pumps or confinement to closed microfluidic channels. These constraints impede their synergy with advanced biofabrication techniques like 3D bioprinting, thereby curtailing the potential to introduce greater complexity into engineered tissues. Herein, a pumpless recirculating platform (UniPlate) that enables unidirectional media recirculation through 3D printed tubular tissues, is demonstrated.The device is made of polystyrene via injection molding in combination with 3D printed sacrifical gelatin templates. Tubular blood vessels with unidirectional perfusion are firstly engineered. Then the design is expanded to incorporate duo-recirculating flow for culturing vascularized renal proximal tubules with glucose reabsorption function. In addition to media recirculation, human monocyte recirculation in engineered blood vessels is also demonstrated for over 24h, with minimal loss of cells, cell viability, and inflammatory activation. UniPlate can be a valuable tool to more precisely control the cellular microenvironment of organ-on-a-chip systems for drug discovery.

T-Cadherin Deficiency Is Associated with Increased Blood Pressure after Physical Activity.

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the Cdh13 gene to be associated with hypertension. However, the role of T-cadherin in regulating blood pressure has not been experimentally elucidated. Herein, we generated Cdh13∆Exon3 mice lacking exon 3 in the Cdh13 gene and described their phenotype. Cdh13∆Exon3 mice exhibited normal gross morphology, life expectancy, and breeding capacity. Meanwhile, their body weight was considerably lower than of WT mice. When running on a treadmill, the time spent running and the distance covered by Cdh13∆Exon3 mice was similar to that of WT. The resting blood pressure in Cdh13∆Exon3 mice was slightly higher than in WT, however, upon intensive physical training their systolic blood pressure was significantly elevated. While adiponectin content in the myocardium of Cdh13∆Exon3 and WT mice was within the same range, adiponectin plasma level was 4.37-fold higher in Cdh13∆Exon3 mice. Moreover, intensive physical training augmented the AMPK phosphorylation in the skeletal muscles and myocardium of Cdh13∆Exon3 mice as compared to WT. Our data highlight a critically important role of T-cadherin in regulation of blood pressure and stamina in mice, and may shed light on the pathogenesis of hypertension.

Arsenic trioxide demonstrates efficacy in a mouse model of preclinical systemic sclerosis

BackgroundUncontrolled T-cell activation plays a key role in systemic sclerosis (SSc). Arsenic trioxide (ATO) has immunological effects and has demonstrated potential in preclinical SSc models. In this study, we assessed the efficacy of ATO in Fra2 transgenic (Fra2TG) mice, which develop severe vascular remodeling of pulmonary arterioles and nonspecific interstitial pneumonia-like lung disease, closely resembling human SSc-associated pulmonary hypertension, therefore partially resembling to the SSc human disease.MethodsThe efficacy of ATO in Fra2TG mice was evaluated through histological scoring and determination of cell infiltration. Fibrotic changes in the lungs were assessed by measuring collagen content biochemically, using second harmonic generation to measure fibrillar collagen, and imaging via computed tomography. Cardiovascular effects were determined by measuring right ventricular systolic pressure and vessel remodeling. The mechanism of action of ATO was then investigated by analyzing lung cell infiltrates using flow cytometry and bulk RNA with sequencing techniques.ResultsAfter ATO treatment, the Ashcroft histological score was substantially decreased by 33% in ATO-treated mice compared to control mice. Other investigations of fibrotic markers showed a trend of reduction in various measurements of fibrosis, but the differences did not reach significance. Further cardiovascular investigations revealed convergent findings supporting a beneficial effect of ATO, with reduced right ventricular systolic pressure and medial wall thickness, and a significant decrease in the number of muscularized distal pulmonary arteries in ATO-treated Fra2TG mice compared to untreated Fra2TG mice. Additionally, inflammatory cell infiltration was also markedly reduced in lesioned lungs. A reduction in the frequency of CD4 + and T effector memory cells, and an increase in the percentage of CD4 + T naive cells in the lungs of ATO-treated Fra-2TG mice, was observed when compared to PBS group Fra-2Tg mice. RNA-seq analysis of ATO-treated mouse lungs revealed a downregulation of biological pathways associated with immune activity and inflammation, such as T-cell activation, regulation of leucocyte activation, leucocyte cell–cell adhesion, and regulation of lymphocyte activation.ConclusionsOur results suggest the clinical relevance of ATO treatment in SSc. Using the Fra2TG mouse model, we observed significant lung histological changes, a trend towards a decrease in various fibrotic makers, and a strong reduction in vascular remodeling. The mechanism of action of ATO appears to involve a marked counteraction of the immune activation characteristic of SSc, particularly T-cell involvement. These findings pave the way for further studies in SSc.

Lymph Vessels Associate with Cancer Stem Cells from Initiation to Malignant Stages of Squamous Cell Carcinoma.

Tumor-associated lymph vessels and lymph node involvement are critical staging criteria in several cancers. In skin squamous cell carcinoma, lymph vessels play a role in cancer development and metastatic spread. However, their relationship with the cancer stem cell niche at early tumor stages remains unclear. To address this gap, we studied the lymph vessel localization at the cancer stem cell niche and observed an association from benign skin lesions to malignant stages of skin squamous cell carcinoma. By co-culturing lymphatic endothelial cells with cancer cell lines representing the initiation and promotion stages, and conducting RNA profiling, we observed a reciprocal induction of cell adhesion, immunity regulation, and vessel remodeling genes, suggesting dynamic interactions between lymphatic and cancer cells. Additionally, imaging analyses of the cultured cells revealed the establishment of heterotypic contacts between cancer cells and lymph endothelial cells, potentially contributing to the observed distribution and maintenance at the cancer stem cell niche, inducing downstream cellular responses. Our data provide evidence for an association of lymph vessels from the early stages of skin squamous cell carcinoma development, opening new avenues for better comprehending their involvement in cancer progression.

Extracellular matrix metalloproteinases inducer gene polymorphism and reduced serum matrix metalloprotease-2 activity in preeclampsia patients.

Preeclampsia increases the risk of pregnancy-related complications, nevertheless a successful spiral vessel remodeling, and trophoblast invasion reduces disorders of pregnancy. Matrix metalloproteinase-2 (MMP-2) clears the path for trophoblast invasion, and activation of MMP-2 largely depends on extracellular matrix metalloproteinases inducer (EMMPRIN) protein. This study aimed to investigate EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia patients. Archival whole blood and serum samples of 74 preeclampsia and 66 normotensive pregnant women age-matched were used in this case-control study. Genomic DNA was extracted from the whole blood samples and EMMPRIN gene amplified with specific primers following fragments sequence mutation analysis. Serum MMP-2 activity was determined using enzyme-linked immunosorbent assay (ELISA) and socio-demographic data of participants retrieved from the database. Age of preeclampsia patients (32.78 ± 6.39) years and body mass index (BMI) (33.09 ± 7.27) kg/m2 compared with the normotensive counterparts (32.33 ± 5.56) years and (32.33 ± 5.56) kg/m2,respectively, were not statistically significant (P > 0.05). Serum matrix metalloprotease-2 (MMP-2) activity was significantly reduced in preeclampsia group (16.34 ± 7.07) compared with the normotensives (25.63 ± 4.56) (P < 0.001), and rs424243T/G variant (55.6%) was overrepresented among the cases compared with the normotensives (16.7%). The single-nucleotide polymorphism T/G was found to be associated with preeclampsia (odds ratio [OR] = 7.63; 95% confidence interval [CI] = 3.95-14.75; P < 0.0001). Decreased activity of MMP-2 and rs424243T/G SNP of EMMPRIN gene was reported in preeclampsia. These preliminary data warrant a further investigation into the relationship between EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia.

Impact of Asthma Phenotypes on Myocardial Performance and Pulmonary Hypertension in Children and Adolescents With Moderate to Severe Persistent Asthma.

Asthma is characterized by chronic inflammation and remodeling of pulmonary vessels and airway wall resulting in pulmonary hypertension (PH). Increased afterload on right ventricle (RV) myocardium leads to RV diastolic dysfunction (RVDD). Echocardiography is an excellent tool to detect these changes early. Using echocardiography, we assessed the impact of clinical asthma phenotypes on myocardial performance and PH in children with asthma. Sixty children with moderate or severe persistent asthma and 60 age and gender-matched healthy controls were enrolled. As per clinical phenotypes, children with asthma were classified into early wheezers (n = 30) and late wheezers (n = 30). Pulmonary function tests (PFT) and echocardiography, both conventional and pulse wave (PW), were performed. Children with asthma had significant RVDD and higher incidence (33%) of PH. Myocardial performance index (MPI) was poor in asthmatics, 0.41 (0.04) compared to controls, 0.38 (0.03). Measures for PH such as tricuspid regurgitation (TR) gradient, TR velocity, and pulmonary artery pressure (PAP) were significantly higher in cases. Among clinical asthma phenotypes, there was no difference in left ventricular ejection fraction (LVEF) between early 64.3% (4.6) and late wheezers 65.6% (4.4). MPI was better in late wheezers at 0.41 (0.05) than in early wheezers at 0.40 (0.03). TR gradient, TR velocity, and PAP were significantly higher in early wheezers. The odds ratio for the development of PH was 0.74 (CI 0.25 - 2.17), and for the development of RVDD was 3.2 (CI 0.77 - 13.8), both in favor of early wheezers. Children with asthma, particularly early-onset wheezers are at increased risk of developing PH and RVDD. We suggest annual screening by conventional echocardiography and pulse wave Doppler imaging for early diagnosis and timely initiation of management.

Highly reproducible rat arterial injury model of neointimal hyperplasia.

Models of arterial injury in rodents have been invaluable to our current understanding of vessel restenosis and play a continuing role in the development of endovascular interventions for cardiovascular disease. Mechanical distention of the vessel wall and denudation of the vessel endothelium are the two major modes of vessel injury observed in most clinical pathologies and are critical to the reproducible modelling of progressive neointimal hyperplasia. The current models which have dominated this research area are the mouse wire carotid or femoral injury and the rat carotid balloon injury. While these elicit simultaneous distension of the vessel wall and denudation of the luminal endothelium, each model carries limitations that need to be addressed using a complementary injury model. Wire injuries in mice are highly technical and procedurally challenging due to small vessel diameters, while rat balloon injuries require permanent blood vessel ligation and disruption of native blood flow. Complementary models of vascular injury with reproducibility, convenience, and increased physiological relevance to the pathophysiology of endovascular injury would allow for improved studies of neointimal hyperplasia in both basic and translational research. In this study, we developed a new surgical model that elicits vessel distention and endothelial denudation injury using sequential steps using microforceps and a standard needle catheter inserted via arteriotomy into a rat common carotid artery, without requiring permanent ligation of branching arteries. After 2 weeks post-injury this model elicits highly reproducible neointimal hyperplasia and rates of re-endothelialisation similar to current wire and balloon injury models. Furthermore, evaluation of the smooth muscle cell phenotype profile, inflammatory response and extracellular matrix within the developing neointima, showed that our model replicated the vessel remodelling outcomes critical to restenosis and those becoming increasingly focused upon in the development of new anti-restenosis therapies.

Involvement of metalloproteinase and nitric oxide synthase/nitric oxide mechanisms in early decidual angiogenesis-vascularization of normal and experimental pathological mouse placenta related to maternal alcohol exposure.

Successful pregnancy for optimal fetal growth requires adequate early angiogenesis and remodeling of decidual spiral arterioles during placentation. Prior to the initiation of invasion and endothelial replacement by trophoblasts, interactions between decidual stromal cells and maternal leukocytes, such as uterine natural killer cells and macrophages, play crucial roles in the processes of early maternal vascularization, such as proliferation, apoptosis, migration, differentiation, and matrix and vessel remodeling. These placental angiogenic events are highly dependent on the coordination of several mechanisms at the early maternal-fetal interface, and one of them is the expression and activity of matrix metalloproteinases (MMPs) and endothelial nitric oxide synthases (NOSs). Inadequate balances of MMPs and nitric oxide (NO) are involved in several placentopathies and pregnancy complications. Since alcohol consumption during gestation can affect fetal growth associated with abnormal placental development, recently, we showed, in a mouse model, that perigestational alcohol consumption up to organogenesis induces fetal malformations related to deficient growth and vascular morphogenesis of the placenta at term. In this review, we summarize the current knowledge of the early processes of maternal vascularization that lead to the formation of the definitive placenta and the roles of angiogenic MMP and NOS/NO mechanisms during normal and altered early gestation in mice. Then, we propose hypothetical defective decidual cellular and MMP and NOS/NO mechanisms involved in abnormal decidual vascularization induced by perigestational alcohol consumption in an experimental mouse model. This review highlights the important roles of decidual cells and their MMP and NOS balances in the physiological and pathophysiological early maternal angiogenesis-vascularization during placentation in mice.

DNAzyme Nanoconstruct-Integrated Autonomously-Adaptive Coatings Enhance Titanium-Implant Osteointegration by Cooperative Angiogenesis and Vessel Remodeling.

Orthopedic implants have a high failure rate due to insufficient interfacial osseointegration, especially under osteoporotic conditions. Type H vessels are CD31+EMCN+ capillaries with crucial roles in mediating new bone formation, but their abundance in osteoporotic fracture site is highly limited. Herein, we report a nanoengineered composite coating to improve the in situ osseointegration of a Ti implant for osteoporotic fracture repair, which is realized through inhibiting the stimulator of interferon genes (STING) in endothelial cells (ECs) to stimulate type H vessel formation. Autonomously catalytic DNAzyme-ZnO nanoflowers (DNFzns) were prepared through rolling circle amplification (RCA) of STING mRNA-degrading DNAzymes, which were then integrated on the Ti surface and further sequentially complexed with thioketal-bridged polydopamine and naringenin (Ti/DNFzn/PDA-Nar). ECs and mesenchymal stem cells (MSCs) can be recruited to the implant surface by galvanotaxis, accounting for the negative charges of DNFzn/PDA-Nar, subsequently released Nar under reactive oxygen species (ROS) stimulation to upregulate endothelial nitric oxide synthase (eNOS) in recruited ECs, leading to enhanced local angiogenesis. Meanwhile, the coordinately released DNFzns would abolish STING expression in ECs to transform the newly formed vessels into Type H vessels, thus substantially promoting the osseointegration of Ti implants. This study provides application prospects for improving implant osteointegration for osteoporotic fracture treatment.

A topological data analysis study on murine pulmonary arterial trees with pulmonary hypertension

Pulmonary hypertension (PH), defined by a mean pulmonary arterial blood pressure above 20 mmHg in the main pulmonary artery, is a cardiovascular disease impacting the pulmonary vasculature. PH is accompanied by chronic vascular remodeling, wherein vessels become stiffer, large vessels dilate, and smaller vessels constrict. Some types of PH, including hypoxia-induced PH (HPH), also lead to microvascular rarefaction. This study analyzes the change in pulmonary arterial morphometry in the presence of HPH using novel methods from topological data analysis (TDA). We employ persistent homology to quantify arterial morphometry for control and HPH mice characterizing normalized arterial trees extracted from micro-computed tomography (micro-CT) images. We normalize generated trees using three pruning algorithms before comparing the topology of control and HPH trees.This proof-of-concept study shows that the pruning method affects the spatial tree statistics and complexity. We find that HPH trees are stiffer than control trees but have more branches and a higher depth. Relative directional complexities are lower in HPH animals in the right, ventral, and posterior directions. For the radius pruned trees, this difference is more significant at lower perfusion pressures enabling analysis of remodeling of larger vessels. At higher pressures, the arterial networks include more distal vessels. Results show that the right, ventral, and posterior relative directional complexities increase in HPH trees, indicating the remodeling of distal vessels in these directions. Strahler order pruning enables us to generate trees of comparable size, and results, at all pressure, show that HPH trees have lower complexity than the control trees.Our analysis is based on data from 6 animals (3 control and 3 HPH mice), and even though our analysis is performed in a small dataset, this study provides a framework and proof-of-concept for analyzing properties of biological trees using tools from Topological Data Analysis (TDA). Findings derived from this study bring us a step closer to extracting relevant information for quantifying remodeling in HPH.

Pilot Study: FSHR Expression in Neuroendocrine Tumors of the Appendix.

Appendix neuroendocrine neoplasm (ANEN) treatment is based on tumor size and proliferation markers. Recently, the role of the follicle-stimulating hormone receptor (FSHR) from the clinical perspective has also been increasingly discussed. The FSHR is expressed in the endothelial cells of both intratumoral and peritumoral blood vessels, where it contributes to neoangiogenesis and blood vessel remodeling. FSHR expression is associated with a range of tumor types, such as gastrointestinal tumors, and it is not detected in healthy tissues located more than 10 mm from the tumor site or in tumor lymphatics. In this study, we evaluated the expression of FSHR and CD31 in the blood vessels of ANENs in females and males with confirmed histopathology. We conducted a quantitative analysis of the immunohistochemical reactions and found a higher number of microvessels in the mucosa and submucosa of neuroendocrine tumors in the appendix. A higher level of FSHR expression was observed in women. Future research should consider whether an elevated number of blood vessels along with a strong pattern of FSHR expression may influence future treatment strategies.